The widespread, growing illicit use of cocaine justifies a close study of the mechanism of action by which cocaine produces its pharmacological and behavioral effects. Recent experiments in our institute indicate the presence of binding sites for cocaine in mouse brain. This binding was found to be saturable, relatively specific and inhibitable by endogenous peptides. We propose to characterize the cocaine binding sites biochemically and pharmacologically, addressing the question of whether the binding site really represents a pharmacological receptor according to criteria of saturability, specificity, and pharmacology. We therefore propose the following studies: 1. Correlation studies. Various cocaine derivatives and analogs will be assayed for their potency in inhibiting cocaine binding in vitro, and for their behavioral activity (locomotor activity, reversal of reserpine-induced eyelid ptosis, increase of stereotyped gnawing response to apomorphine), to establish whether there is a correlation between the binding data and the central effects. Penetration and enzymatic degradation of the compounds administered in vivo will be studied since the pharmacological activity is related to the amount of drug that reaches the locus of action and to its sensitivity towards degrading enzymes. 2. Distribution studies. Cocaine binding will be compared among a., tissues, to investigate whether the central activities corrrelate only with the central binding; b., brain regions, to examine cocaine binding sites topographically and to look for a possible relationship with catecholaminergic or other neurotransmission systems; c., subcellular fractions, to assess whether the cocaine binding sites are localized in the synapse and if so, subsynaptosomal fractions, to determine their location within the synapse; and d., various inbred mouse strains, to examine which cocaine response distributes among the strains in parallel with the cocaine binding. 3. Regulation studies. We will test the changes in cocaine binding in vitro upon chronic treatment with cocaine in vivo and compare those with concomitant changes in behavior.